Sphingolipids are important mediators and regulators of cell signaling pathways. Our studies have focused on the actions of two classes of sphingolipids represented by glycosphingolipids and sphingosine-1-phosphate. Our work is aimed at defining the normal functions of these sphingolipids and understanding their roles in disease processes. Glycosphingolipids (GSLs) are found in the outer leaflet of the plasma membrane and are concentrated in specialized signaling structures. They are particularly abundant in neuronal cells in the form of gangliosides (sialic acid containing GSLs). Through genetic disruption of genes that encode synthetic enzymes for GSLs, we have created a series of mice that express limited glycosphingolipid structures. We are using these mice to discover the functions of GSLs. When the cellular machinery responsible for GSL degradation is defective, GSL storage diseases result in which profound neurodegeneration occurs. Examples are Tay-Sachs and Gaucher diseases. We are attempting to understand how the accumulation of GSLs cause neurodegeneration through the construction of animal models of the diseases. Recent experiments have led to a model of neurodegeneration in GSL storage diseases with inflammation as an important component. Sphingosine-1-phosphate is a bioactive sphingolipid metabolite that binds to a family of G-protein-coupled receptors, known as S1P receptors. Stimulation of SIP receptors triggers diverse cellular effects. We are disrupting S1P receptors and the enzymes that produce sphingosine-1-phosphate to discover the physiological functions of this signaling system. We have uncovered a unique role for this lipid signaling pathway in the formation of blood vessels during development.